Abstract 2479: Preclinical assessment of imaging agents for identification of fucosyl-GM1 expression <i>in vivo</i>
Authors: R. Adam Smith, Erin L. Cole, Andrea Olga Shorts, Thomas Petrone, Joonyoung Kim, Daniel Cohen, Paul Morin, Samuel J. Bonacorsi, Patrick L. Chow
Journal: Cancer Research (2022)

Abstract Background: Fucosyl-GM1 (FucGM1) is a monosialoganglioside highly expressed in 50%-70% of small cell lung cancer (SCLC) cells, supporting it as a potential biomarker. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to FucGM1 with high affinity and specificity. Understanding how FucGM1+ tumor expression correlates with response to BMS-986012 may improve patient selection and therapeutic efficacy. Objective: Evaluate ability of imaging agents built on BMS-986012 to detect tumor FucGM1 expression. Methods: BMS-986012 was labeled with a near-infrared fluorophore. Binding to human H520 (FucGM1−) and DMS79 (FucGM1+) xenografts was assessed in vivo via optical imaging. BMS-986012 was labeled with deferoxamine and radiolabeled to produce 89Zr-BMS-986279, which was evaluated in vitro with H520 and DMS79 cells. Tracer distribution and tumor accumulation was assessed by positron emission tomography (PET) imaging in mice bearing bilateral H520 and DMS79 xenografts and analyzed with ex vivo autoradiography (ARG). Results: Optical imaging with fluorescent BMS-986012 showed statistically significant accumulation in DMS79 vs H520 tumors at all time points (P&amp;lt;.05), beginning 6 hours post administration and reaching a 3:1 maximum uptake ratio. Maximum tumor to background signal was measured at 96 hours (final imaging time point). Total radiolabeled 89Zr-BMS-986279 binding to intact DMS79 cells was ≈15-fold higher than to H520 control cells in vitro and was almost completely blocked by coincubation with a 1000-fold excess of BMS-986012. In vivo, longitudinal PET imaging of 89Zr-BMS-986279 showed significantly higher tracer accumulation in FucGM1+ DMS79 xenografts vs H520 tumors (P&amp;lt;.001). The difference in tracer uptake between tumor models increased with time and was highest (≈2-fold) approximately 8 days post injection. PET signal decreased over time in both FucGM1− H520 xenografts and background muscle tissues, consistent with slow accumulation of specific binding and clearance from background common with antibody-based tracers. Ex vivo ARG studies confirmed in vivo PET results and indicated that 89Zr-BMS-986279 can be used to assess FucGM1 expression throughout the tumor volume, with signal found in the periphery and interior of tumor samples. Conclusions: In vitro cell binding, in vivo fluorescence and PET imaging, and ex vivo ARG studies demonstrated that 89Zr-BMS-986279 was sensitive and specific for detecting FucGM1 expression in tumor cells. Specificity to the intended target in animal disease models coupled with kinetics typical of antibody-based tracers further support the utility of 89Zr-BMS-986279 as a potential FucGM1 imaging agent. A phase 2 study is evaluating safety and efficacy of BMS-986012 combined with carboplatin, etoposide, or nivolumab in patients with newly diagnosed extensive-stage SCLC (NCT04702880). Citation Format: R. Adam Smith, Erin L. Cole, Andrea Olga Shorts, Thomas Petrone, Joonyoung Kim, Daniel Cohen, Paul Morin, Samuel J. Bonacorsi, Patrick L. Chow. Preclinical assessment of imaging agents for identification of fucosyl-GM1 expression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2479.